Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics
Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics
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DOI：
10.1038/s41557-019-0237-6
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发表时间：
2019-06-01
期刊：
影响因子：
21.8
通讯作者：
Tate, Edward W.
中科院分区：
文献类型：
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作者：
Storck, Elisabeth M.;Morales-Sanfrutos, Julia;Tate, Edward W.
C-末端半胱氨酸残基处的翻译后法尼基化或香叶基香叶基化调节超过100种蛋白质（包括Ras同种型）的定位和功能，并且是包括癌症和感染在内的疾病中的治疗靶标。在这里，我们报告的全球和选择性的异戊二烯化的蛋白质在活细胞中的发展，使类异戊二烯类似物YnF和YnGG结合定量化学蛋白质组学。在单个人类细胞系中鉴定了80种异戊二烯化蛋白，64种首次在内源丰度下没有代谢干扰。我们进一步证明，YnF和YnGG能够直接识别后处理的异戊二烯化肽，异戊二烯化动力学和替代异戊二烯化的蛋白质组范围内的定量分析，以响应四种不同的异戊二烯基转移酶抑制剂，和定量的视网膜退行性疾病模型中的Rab异戊二烯化缺陷。
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.